Mental retardation (MR), for which few effective treatments are available, is a common manifestation of developmental brain disorders. This proposal is based on the hypothesis that pharmacological correction of neuronal defects of morphology or plasticity will enhance the acquisition of cognitive skills in MR patients. Mutations of many different genes can cause MR, and many MR genes are members of interconnected genetic pathways that are very highly conserved among animal species. Such conservation provides an opportunity to use genetic model systems to explore novel therapeutic strategies prior to clinical testing. We have developed a primary cell culture assay for identification of abnormal morphology or plasticity of brain neurons with MR-gene mutations, as well as for identification of compounds that normalize the defects. The neurons are from fruit fly (Drosophila melanogaster) mushroom bodies, the best-characterized insect brain region involved in learning and memory, harvested during a stage of peak steroid-hormone-dependent developmental plasticity. When wild-type neurons are cultured in vitro they elaborate an arbor with a highly stereotyped morphology. The assay has revealed normal sexual dimorphism, as well as phenotypes due to single-gene mutations. In some cases, the in vitro culture system is highly sensitive, unmasking defects whose in vivo manifestations are too subtle to be detected by conventional microscopy. To enhance the speed of screening, we are developing NeuronMorphometrics, a set of Java plug-ins for ImageJ that perform semi-automated data analysis. About 75% of human MR genes have a counterpart in Drosophila that is similar enough by sequence to plausibly perform similar functions in the brain. We will screen a subset of Drosophila MR genes which we believe are prime candidates for revealing neuronal morphology and plasticity defects in vitro. In parallel studies, we will focus on the "filagree" phenotype, an abnormal mode of neurite outgrowth in vitro due to genetic loss of a cytoskeletal protein, and screen for compounds that normalize this phenotype. Together, the screens for phenotypes and for corrective chemical agents should set the stage for use of this assay as a stepping stone for drug discovery and development for MR disorders. Public health relevance: Our long-term goal is to treat mental retardation disorders with drugs that fix the underlying abnormalities of brain development. The proposed experiments are an important step toward that goal. [unreadable] [unreadable] [unreadable]